Certificate of correction



1925. f mwmnzms Jean Druey, Riehen, and Paul Schmidt, Therwil, Switzer- Ciba Pharmaceutical Products lnc land, assignors to Summit, NJ.

No Drawing. Application January 2, 1958 Serial No. 706,591

Claims priority, application Switzerland January 14, 1957 v 7 Claims. (Cl. 260-2495) 7 This invention relates to new v-triazines. More particularly the invention concerns v-triazines of the formula I Ar ' in which Ar represents an aryl residue,-'and ta'utome'ric forms of-these compouridsfand also their substitutioh "productsin which the tautomerizing hydrogen atom 'is replaced by a substituent, andsalts of these compounds. In the aforesaid new'compoundsflthe varyl residuevis preferably an unsubstituted phenyl' radical or a phenyl radical substituted, forv example, by a halogen atom, such acid nitrile with the appropriate arylliydrazineand hy drolysisof the obtained 2-aryl-3-amino 4 cyano pyrazol Serial No.

i stro'ng inorganic or, organic acids, forexample hydrohalic a acids, sulfuric acid or organic sulfonic acids, for example,

benzene sulfonic acids. The preferred substitutingagents are lower alkyl halides, such as chlorides,.bromides. or

iodides.

Depending on the reaction conditions the. new compounds-are obtained in the free formor in the form of salts thereof, and the free compounds can be converted into their salts or vice versa. Thus, the free bases'may ,be converted'into their therapeutically acceptable salts,

' for example, by reaction with inorganic or organic acids,

as chlorine, bromine or fluorine or a lower alkoxy or alkyl group, such as a methyl, methoxy, propyl or propoxy radical. The substituent at the hetero-atom in the pyrim:

,idin ring is more especiallya lower aliphatic radical; A carriersjthe're are 'jlsed substances which do "not react newcornpounds' for'example;'gelatineylacto'se,s

low aliphatic radical is, for example, a'lower hydrocarbon radical in which a carbon. atom .no'tbouridto the hetero-atomis replaced by a hetero a'tom suchas nitro-' gen, for example, a lower tertiarylaminoalkyl-g-roup, such as a lower dialkylaminoalkyl, e.g. dimethylam'inoethyl group Preferably,lhowever, the 'aliphaticradical 's ilafm'. lower, alkyl group such as methyl,

Thej new, vv-triaaines have, valu ble ipharmacological j properties, especially a diuretic action, '(lon segue'ntly, Q

they are useful as medicaments... Theyare alsouable intermediate product s for,.the'.manu facture of inedica ments..;. Most active as diuretics,.and therefore forming aspecific. and preferred embodiment of the invention distinguished from the' other forms 'of'thezinvention are the v-triazines of the formula V phenyl-4 oxo-5-me thyl 51,5 dihydro-py zoloi3' v-triazine.. ji' The new compounds tuted 2 -aryl-3-unsubstituted aminopyr'azole 4-carboxylic acid amide with a diazotizing agent, such'as nitrous acid or-a salt thereof in the, presence of an acid. Therea'care made'fby treatinga S- unsulisti-Y tion is carried out in a mannerknown for diazo'tizing" obtained by reaction of ethoxymethylene-cyano-acetic sions or emulsions.

such ashydrohalic acids, sulfuric acid, nitric acid, perchlo'ric acid, phosphoric acids, formic acid, acetic acid, propionic acid, lactic acid, oxalicacid, succinic acid,

I inalic acid, tartaric acid, citric acid, ascorbic acid, meth I ane sulfonic acid, ethane sulfonic .acid, oxyethane sulpreparations contain the new compound in admixture flwith, afph'armaceutical organic orinorganiclcarrieisuit ableifor enteral'o'r parenterali administration. As the ate 'r', magnesium stearate, talc, vegetable oils,

of other i known carriers forfm'edicaments. The pharma ceutical preparations may be, f for example, in the form r v of tablets, dragee's orin liquid form as solutions, suspen,- A.

If desired they' maybe sterilized and/or may conta'in auxiliary substancesisuch as preserving,stabilizing,'wetting or emulsifying agents. They may 'also' contain othentherapeutically valuable substances;

methods.

' The following examples illustrate the invention: 7

Ex p r r A. solution of 20 grains of 2 phenyl 3 amino-r 4-carbamyl-pyrazole in '150 cc.-of ZN-hydrochlotic 'acid is: mixed at 0-10 C. with 6.9 grains of sodium nitrite dissolved in cc. of .watenwhereby a yellowprecipitate p 7 separates out; In-order to complete the reaction the whole, 7

1 g a I I 7 r is stirred for a further 2 hours at room temperature, then -wherein Ph stands for phenyl,'halogeno-phenyl, alkoxyff:

phenyl or alkyl-phenyl, and their substitution'products"in which the tautomerizing hydrogen is r'e'placed'by a. lower,

alkyl group, preferably methyh- [and ,more, particularly l-phenyl 4-- hydrox'y-pyrazoloBi l d] ij-triazinev sand the precipitated product'is filtered off with'suction washed'with water. It' is recrystallized from 'alcohol to yield i.1 pheny1-4 hydroxy-pyrazolo[3j4-dl v-triazine;- of

in the-form of yellowish crystals melting at 136 C. with decomposition. 1 g The starting material 1' 24:4 parts'of ethoxymethylenemalonic acid'dinitrile' are can beobtained as :followsi reare e. is .1

The preparations are made up by the usual 3 dissolved in 250 parts by volume of ethyl, alcohol. The

solution is then slowly mixed with 2.2 parts of phenyl- The reaction mass hydrazine and boiled for 10 hours.

7 water are added'to a solution of 12 grams of 2-para-.

is allowed to cool, after which a crystalline product precipitates which is separated by filtering with suction. By recrystallization from alcohol there is obtained 2-phenyl- 3-amino-4-cyanopyrazole of the formula obtained in the form of crystals melting at l67l68 C.

Example 2 10.6 grams of l-phenyl-4-hydroxy-pyrazolo-[3:4-dlvtriazine are introduced into a sodium methylate solution prepared from 1.2 grams of sodium and 400 cc. of anhydrous alcohol. In order to form the sodium salt the mixture is stirred for 3 hours at room temperature. 7.2 grams of chlorethyl-dimethylarnine are added to the suspension so formed, the Whole is heated at the boil for 6 hours, then evaporated to dryness in vacuo, and the residue is dissolved in water and extractedwith chloroform. The chloroform is evaporated from the extract and the residue is recrystallized from isopr'opylether to yield 1 phenyl-S -dimethylaminoethyl-4-oXo- :5 -dihydropyrazolo[3 :4-d]v-triazine of the formula (C Ha) 2N C zHr- N N N A in the form of crystals melting at 103-105" C.

Example 3 7.4 grams of dimethyl sulfate are added to a solution of 10 grams of l-phenyl-4-hydroXy-pyrazolo-[3:4-d] -vtriazine in 50 cc. of a2 N-solution of caustic soda, while stirring and cooling with ice. The whole is allowed to stand for 5 hours at room temperature; and then the precipitate is filtered off with suction. The'precipitate is recrystallized from a large'quantity of petroleum ether to yieldv l phenyl-S-methyl-4-oXo-42S-dihydropyrazoloB:4- dlv-triazine of the formula chloro-phenyl-3-amino-4-carbamyl-pyrazole in cc. of 2 N-hydrochloric acid at 0-10 (3., ayellow precipitate separating off. In order to complete the reaction the whole is stirred for 2 hours at room temperature, the precipitate is filtered ofi? with suction and washed with water. It is recrystallized from ethanol, and l-para-chloro-phenyl- 4-hydroxy-pyroxy-pynazolo l3,4-dlv triazine of the formula is obtained in the form of yellow crystals melting at C. with decomposition.

The 2 para-chlorophenyl-S-amino-4-carbamyl-pyrazole used as starting material is prepared in the following mannew A solution of 55 grams of para-chlorophenylhydrazine in 250 cc. of ethanol is added to a'solution of 47 grams of ethoxymethylene-malonitrile in 500 cc. of ethanol.

The reaction solution is boiled under reflux for 4 hours. It is then allowed to cool and the Z-para-chlorophenyl- 3-amino-4-cyano-pyrazole of the formula N. HaN N formed is filtered with suction. it melts at -171 c.

in the formjof'white crystals melting at 203 204 C.

. What is claimed is:

1. Compounds of the formula wherein Ar represents phenyl and R represents a lower alkyl radical. 7

2. 1-phenyl-5-methy1-4 oxo 4,5 dihydro pyrazolo- (3,4-d)v-triazine. I 1 i 3. 1-pheny1-4-hydroxy-pyramlo(3,4-d)v-triazine. 4. l-phenyl-S dimethylaminoethyl 4 oxo 4,5 dihydro-pyrazolo(3,4-d) v-triazine.

5. l-p chlorophenyl 4 hydroxy triazine. V a

6. Compounds of the formulae:

pyrazolo(3,4-d) vwherein Ar represents a member selected from the group I consisting of phenylrhalogenmphenyl, lower alkyl phenyl and lower alkoxy phenyl and R represents a member- References Cited in the file of this patent Iustoni: Gazz. chim. ItaL, v01. 68, pp. 64-66, 7273, 75 (1938).

UNITED- smrltmm I CERTIFICATE; OF CORRECTION Patent No. '2 925 418 v I i i i I 7 Jean Drueyetv -al February 16} 1960 errorappearfi in the printed specification. a

It is hereby certified that" ing correction and that the said Letters of the above numbered'patent requir Patent should read--- as corrected below.

strike out '"pyroxy";,lines 55to"63 9 below instead of'as in the Column 4, line '8, the formula should appear as shown patent:

Signed and sealed this 10th day of January 1961;

(SEAL) I Attest: i KARL H. AXLINE a I ROBERT ct. WATSON v I Commissioner of Patents Att'esting Officer 

6. COMPOUNDS OF THE FORMULAE: 